Long-Term Safety and Survival Outcomes of [225Ac]Ac-PSMA (Prostate-Specific Membrane Antigen) and [225Ac]Ac-/[177Lu]Lu-PSMA (TANDEM) Radioligand Therapy (PRLT) in Metastatic Castration-Resistant Prostate Cancer.

This study aims to retrospectively assess the safety of [225Ac]Ac-PSMA-PRLT, both as monotherapy and in combination (TANDEM) with Lutetium-177, concerning tolerance after the radiopharmaceutical administration and long-term safety, its impact on salivary glands' function, overall survival (OS), and follow-up duration. Between December 2020 and September 2024, 89 patients received a total of 151 cycles of [225Ac]Ac-PSMA-PRLT. Patients with at least one follow-up (n = 71) were included in the analysis to evaluate xerostomia, as well as long-term hematological, renal, and hepatic toxicities, graded according to CTCAE v5.0. The most common adverse event after the radiopharmaceutical administration was flare pain (n = 16). As of the time of analysis, 68 patients had passed away (76.4%; range of survival 5 days to 39 months, median 7 months), while 21 patients were still alive (23.6%; follow-up duration: 1-33 months). Severe (G3/G4) long-term adverse events were rare, with 15 cases of G3 anemia (21.1%), 6 cases of G3 leukocytopenia (8.4%), and 14 cases of G3/G4 thrombocytopenia (19.7%). Hematological toxicity was primarily associated with severe bone marrow involvement or prior chemotherapy. Additionally, one case of G3 nephrotoxicity (1.4%) and six cases of G3 hepatotoxicity (8.4%) were observed. Only nine patients (12.7%) reported de novo xerostomia (G1/G2). In conclusion, this study demonstrates that [225Ac]Ac-PSMA PRLT, both as monotherapy and combined with [177Lu]Lu-PSMA as TANDEM PRLT, is generally safe in terms of both tolerance after the radiopharmaceutical administration and long-term toxicity.